NOTCH signalling is a key development pathway whose aberrant activation is known to play a role in multiple human cancers. In human tumors the NOTCH pathway can be activated by various genetic lesions such over expression of ligands/receptors, GOF mutations in NOTCH receptors, including protein stabilizing mutations in the PEST domain of NOTCH, chromosomal translocations, or loss-of-function mutations in the E3 ubiquitin ligase FBXW7 and other negative regulators of the pathway (SPEN, NUMB). Activation of signalling due to above mentioned mechanisms can be addressed in part using blocking antibodies against NOTCH ligands/receptors or small molecule inhibitors of the gamma secretase enzyme (GSIs). However, in human tumors where NOTCH signalling is constitutively activated due to chromosomal translocations in the NOTCH receptors (NOTCH1 and 2), none of the above-mentioned strategies will be effective. Moreover, due to on-target and off-target toxicities associated with blocking antibodies and GSIs, these anti-NOTCH agents failed to advance in clinical trials, although some of them showed signs of clinical efficacy. Given the role of NOTCH signalling in human tumors, there is a need to identify novel targets in the NOTCH pathway and develop new and more selective anti-NOTCH agents. To inhibit pan-NOTCH signalling in human tumors independently of the mechanisms of NOTCH activation, and in the most downstream part of the pathway, we have previously reported the discovery of a new class of small molecules able to target the NOTCH transcription complex enabling the specific inhibition of NOTCH target gene expression (e.g. cMYC, HES1, DTX1, CCND1). These small molecules act as protein-protein interaction inhibitors, and thereby compromise the assembly of functional NOTCH transcription complex.

Here we present further in vitro and in vivo characterization of the lead molecule CB-103. The anti-cancer activity of CB-103 was extensively profiled in several human cancer cell lines representing NOTCH positive solid tumors, leukemias and lymphomas. Moreover, CB-103 responsiveness of these cell lines correlates with a downregulation of the NOTCH signature following treatment with CB-103. Specifically, we will present data outlining the in vivo pharmacokinetic and pharmacodynamic properties of CB-103.

Citation Format: Rajwinder Lehal, Charlotte Urech, Michele Vigolo, Maximilien Murone, Freddy Radtke. Characterization and profiling of CB-103, a novel small-molecule protein-protein interaction inhibitor targeting the NOTCH transcription complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5799.